Thyroid hormone has numerous functions in development and physiology in vertebrate species. In humans, thyroid hormone abnormalities in development result in mental and physical retardation. Abnormalities in adulthood result in a different range of defects. A fundamental question concerns how this hormone achieves its multiple functions. Thyroid hormone receptors (TR) control a key point at which the hormonal signal is converted into a cellular response. As members of the nuclear receptor family, TRs act as ligand-regulated transcription factors. Our research has addressed the roles of TRs encoded by the Thrb and Thra genes. What do these genes each do and how do they mediate specialized functions in different tissues? Targeted mutagenesis has revealed roles in endocrine function, growth and development, including important and in some cases unexpected roles in the sensory systems for hearing and color vision. We seek to elucidate the mechanisms underlying thyroid hormone actions and to uncover novel functions for this hormone.[unreadable] [unreadable] In addition to the receptors, the actions of thyroid hormone are determined at other key steps. It is therefore expected that other genes cooperate with TR genes. An example is the activation or inactivation of the hormone by deiodinase enzymes, which may exert a powerful level of control in some target tissues. Our studies aim to understand the varied mechanisms that regulate where, when and how thyroid hormone acts.[unreadable] [unreadable] 1. Development of the color visual system. Cone photoreceptors are the sensory cells that mediate color perception, which is achieved by the expression of opsin photopigments with sensitivity to different regions of the visible light spectrum (blue and green in rodents). The generation and differentiation of cone photoreceptors and the choice of which opsin they express are poorly understood processes. We found that a thyroid hormone receptor (TRb2) is essential for the diversification of immature cones into blue and green sub-types. Evidence suggests that cones acquire a blue identity by default and that TRb2 switches a sub-population to become green. Recent findings include evidence for the role of thyroid hormone ligand itself in suppressing or limiting blue opsin expression in immature cones. [unreadable] [unreadable] 2. Thyroid hormone and hearing. The auditory system provides another novel but more complex example of important thyroid hormone actions. Congenital thyroid hormone defects in humans are associated with deafness, although it is not well defined how the hormone acts in this system. Thyroid hormone receptors, especially, those encoded by the Thrb gene contribute to many events in the later stages of postnatal differentiation and onset of function of the cochlea, involving the sensory hair cells and other cell types. Recent studies include an investigation of the role of the Thra receptor gene in hearing and of mutations that may cause deafness. [unreadable] [unreadable] 3. Cooperation of deiodinases and TRs. The identification of genes that modify TR functions should yield insights into how the tissue-specific functions of thyroid hormone are defined. Deiodinase enzymes that activate or inactivate the hormone are candidates that could exert powerful, tissue-specific control over TR activity. In collaboration with Dr. V. Galton (Dartmouth Med. School), evidence suggests that type 2 deiodinase, a thyroid hormone-activating enzyme, is critical for hearing. Recent results also indicate an essential role for type 3 deiodinase, a hormone-inactivating enzyme, in the development of hearing. Type 3 deiodinase also has a critical role in the development of cone photoreceptors. [unreadable] [unreadable] 4. In the broader context, the TR genes may cooperate with other types of gene in directing the development of different systems. Candidates include other types of nuclear receptor. Evidence indicates that the orphan nuclear receptor RORb (retinoid-related orphan receptor b) is involved in retinal photoreceptor development. Unlike TRs, there is no known physiological ligand for RORb, which acts constitutively to regulate transcription of target genes. RORb has some role in retinal neurogenesis photoreceptor development.